Clinical Trials Register

Summary
EudraCT Number:	2016-002208-21
Sponsor's Protocol Code Number:	TP-434-025
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-09-15
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Bulgarian Drug Agency

A.2

EudraCT number

2016-002208-21

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Double-Dummy, Multicenter, Prospective Study to Assess the Efficacy and Safety of Eravacycline Compared with Meropenem in Complicated Intra-abdominal Infections

Фаза 3 рандомизирано, двойно-сляпо, двойно-маскирано, многоцентрово проспективно изпитване за оценка на ефикасността и безопасността на еравациклин в сравнение с меропенем при усложнени интраабдоминални инфекции

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Multicenter Study to Assess the Efficacy and Safety of Eravacycline Compared with an Approved Drug, Meropenem in Complicated Intra-abdominal Infections

Mногоцентрово изпитване за оценка на ефикасността и безопасността на еравациклин в сравнение с одобрен лекарствен продукт меропенем, при усложнени интраабдоминални инфекции

A.3.2

Name or abbreviated title of the trial where available

IGNITE4

A.4.1

Sponsor's protocol code number

TP-434-025

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02784704

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Tetraphase Pharmaceuticals, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Tetraphase Pharmaceuticals, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	PSI Co Ltd.
B.5.2	Functional name of contact point	Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Baarerstrasse 113
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	6300
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+7812320 38 550446
B.5.5	Fax number	+7812320 38 50
B.5.6	E-mail	Elena.Kalinina@psi-cro.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	eravacycline
D.3.2	Product code	TP-434
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ERAVACYCLINE
D.3.9.1	CAS number	1207283-85-9
D.3.9.2	Current sponsor code	TP-434
D.3.9.4	EV Substance Code	SUB117477
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	53
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	meropenem
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MEROPENEM
D.3.9.1	CAS number	96036-03-2
D.3.9.4	EV Substance Code	SUB08778MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Complicated Intra-abdominal Infections

Усложнени интраабдоминални инфекции

E.1.1.1

Medical condition in easily understood language

Complicated Intra-abdominal Infections

Усложнени интраабдоминални инфекции

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10056570
E.1.2	Term	Intra-abdominal infection
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to compare the clinical response at the test-of-cure (TOC) visit in the microbiological intent-to-treat (micro-ITT) population for subjects in the 2 treatment arms.

E.2.2

Secondary objectives of the trial

1. To compare the clinical response for subjects in the 2 treatment arms at the end-of-treatment (EOT), TOC, and follow-up (FU) visits in the following populations:
- Intent-to-treat (ITT) population
- All-treated (MITT)
- Clinically evaluable (CE) population
- Micro-ITT population (for EOT and FU)
- Microbiologically evaluable (ME) Population

2. To compare the microbiologic response in the treatment arms at the EOT and TOC visits in the following populations:
- Micro-ITT population
- ME Population

3. To assess the safety and tolerability of eravacycline administration in the safety population
4. To explore pharmacokinetic (PK) parameters of eravacycline

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female subject hospitalized for cIAI with one of the following diagnoses:
a. Intra-abdominal abscess: one or more abscesses surrounding diseased or perforated viscera (including hepatic and splenic abscesses)
b. Gastric or intestinal perforation associated with diffuse peritonitis
c. Peritonitis: diffuse infection of the peritoneum (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
d. Appendicitis with perforation, peritonitis or abscess
e. Cholecystitis with perforation or abscess
f. Diverticulitis with perforation, peritonitis, or abscess
Note: Infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligible. Ischemic bowel disease without perforation is not eligible. Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible

2. At least 18 years of age
3. Evidence of a systemic inflammatory response with at least one of the following:
a. Fever (oral, rectal, tympanic, or by temporal artery temperature > 100.4˚F / 38˚C) or hypothermia (temperature ≤ 95.9˚F / 35.5˚C)
b. Elevated WBC (> ULN laboratory range); or proportion of band forms of the WBC differential beyond the ULN laboratory range
c. Increased pulse (HR > 90 beats per minute)
d. Increased respiratory rate (> 20 breaths per minute)
4. Abdominal pain or flank pain (with or without rebound tenderness), or pain caused by cIAI that is referred to another anatomic area such as back or hip, or localized or diffuse abdominal wall rigidity, or mass, or ileus
5. Able to provide informed consent.
6. Subjects must agree to use a highly reliable method of birth control:
a. Male subjects must agree to use an effective barrier method of contraception during the study and for 14 days following the last dose if sexually active with a female of childbearing potential
b. Female subjects must not be pregnant or nursing. For females of childbearing potential, subjects must commit to either:
i. Use at least two medically accepted, effective methods of birth control (eg, condom, oral contraceptive, indwelling intrauterine device, hormonal implant /patch, injections, approved cervical ring, etc.) during study drug dosing and for 14 days following last study drug dose, OR
ii. Sexual abstinence

And either
7A. Meets All Inclusion Criteria for Pre-operative Enrollment:
- Has a sonogram or radiographic imaging result congruent with the diagnosis of cIAI, AND
- Acute surgical or percutaneous intervention (open laparotomy, laparoscopic surgery, or percutaneous drainage of an abscess) is foreseen within 24-h
Or
7B. Meets All Inclusion Criteria for Intra-operative/Post-operative Enrollment:
- Visual confirmation of cIAI (presence of pus within the abdominal cavity), AND
- Surgical intervention includes open laparotomy, laparoscopic surgery, or percutaneous draining of an abscess, AND
- Intervention is adequate (ie, a procedure in which all communications between the GI tract and the peritoneal cavity are closed, no necrotic intestine is left, and all infected collections are drained at the procedure), AND
- Subjects who are enrolled in the trial post-operatively must receive no more than one dose of effective antibacterial drug therapy post-operatively before randomization

E.4

Principal exclusion criteria

1. Considered unlikely to survive the 6-8 week study period
• Any rapidly-progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure and septic shock
• Requirement for vasopressors (prior to enrollment) at therapeutic dosages (ie, dopamine > 5 μg/kg/min, any dose of norepinephrine, epinephrine or phenylephrine) to maintain a systolic blood pressure ≥ 90 mm Hg or a mean arterial pressure ≥ 70 mm Hg following adequate fluid resuscitation
2. Creatinine clearance ≤ 50 mL/min as estimated by the Cockcroft-Gault equation
3. Presence or possible signs of significant hepatic disease:
a. Alanine aminotransferase or aspartate aminotransferase > 5 x ULN, OR
b. Total bilirubin > 3 x ULN, unless isolated hyperbilirubinemia is directly related to the acute process
4. Immunocompromised condition, including known HIV positivity (requiring anti-retroviral therapy or with CD4 count < 300), AIDS, organ (bone marrow) transplant recipients, and hematological malignancy. Immunosuppressive therapy, including use of high-dose corticosteroids (eg, > 20 mg prednisone or equivalent per day for greater than 2 weeks)
5. History of moderate or severe hypersensitivity reactions to tetracyclines, carbapenems, β-lactam antibiotics or to any of the excipients contained in the study drug formulations
6. Participation in any investigational drug or device study within 30 days prior to study entry
7. Known or suspected current central nervous system (CNS) disorder that may predispose to seizures or lower seizure threshold (eg, severe cerebral arteriosclerosis, epilepsy)
8. Antibiotic-related exclusions:
a. Receipt of effective antibacterial drug therapy for cIAI for a continuous duration of > 24-h during the 72-h preceding randomization [However, subjects with documented cIAI (ie, known baseline pathogen) who have received at least 72-h of antibiotic therapy and are considered treatment failures may be enrolled. Treatment failure is defined as persistent fever and/or clinical symptoms; or the development of a new intra-abdominal abscess after ≥ 72-h of antibiotic therapy], OR
b. Receipt of meropenem or any other carbapenem, or tigecycline for the current infection, OR
c. Need for concomitant systemic antimicrobial agents effective in cIAI other than study drug
9. Refusal of mechanical ventilation, dialysis or hemofiltration, cardioversion or any other resuscitative measures and drug/fluid therapy at time of consent
10. Known or suspected inflammatory bowel disease or associated visceral abscess
11. The anticipated need for systemic antibiotics for a duration of more than 14 days
12. Systemic malignancy that required chemotherapy, immunotherapy, radiation therapy or antineoplastic therapy within the previous 3 months or which is anticipated to begin prior to the TOC visit
13. Known at study entry to have cIAI caused by a pathogen(s) resistant to one of the study drugs
14. Any other unstable or clinically significant concurrent medical condition (ie, class IV heart or lung disease, end stage renal disease, or requiring hemodialysis, etc.) that would, in the opinion of the investigator, jeopardize the safety of a subject, impact their expected survival through the end of the study participation, and/or impact their ability to comply with the protocol

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of this study will be the clinical response at the Test-of-cure (TOC) visit in the micro-ITT population.
NOTE: For the EMA, the primary analysis populations will be the all-treated (MITT) and the clinically evaluable (CE) populations.

E.5.1.1

Timepoint(s) of evaluation of this end point

The test-of-cure visit

E.5.2

Secondary end point(s)

- Clinical response at the End of Therapy (EoT), Test-of-cure (TOC) and Follow Up (FU) visits
- Microbiologic response for subjects in the 2 treatment arms at the EOT and TOC visits Version 1.0

E.5.2.1

Timepoint(s) of evaluation of this end point

The End of Therapy, Test-of-Cure and Follow Up visits

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Czech Republic

Estonia

Georgia

Hungary

Latvia

Lithuania

Romania

Russian Federation

Ukraine

United States

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

328

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

138

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Subjects must be able to provide informed consent, however if they are incapable of giving consent personally, for example if they are in emergency due to their medical condition, then the option for a legal representative to sign is available.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

360

F.4.2.2

In the whole clinical trial

466

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Post-operative treatment for subjects who completed his/her participation in the trial is not different from the standard treatment for patients with complicated intra-abdominal infection

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-10-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-10-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-05-19

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